Hostname: page-component-cd9895bd7-jkksz Total loading time: 0 Render date: 2024-12-26T06:55:20.716Z Has data issue: false hasContentIssue false
  • English
  • Français

Enhanced adrenal sensitivity to adrenocorticotrophic hormone (ACTH) is evidence of HPA axis hyperactivity in Alzheimer's disease

Published online by Cambridge University Press:  09 July 2009

J. T. O'Brien ,
D. Ames ,
I. Schweitzer ,
M. Mastwyk  and
P. Colman
J. T. O'Brien*
Affiliation:
Department of Psychiatry and Department of Diabetes and Endocrinology, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
D. Ames
Affiliation:
Department of Psychiatry and Department of Diabetes and Endocrinology, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
I. Schweitzer
Affiliation:
Department of Psychiatry and Department of Diabetes and Endocrinology, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
M. Mastwyk
Affiliation:
Department of Psychiatry and Department of Diabetes and Endocrinology, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
P. Colman
Affiliation:
Department of Psychiatry and Department of Diabetes and Endocrinology, University of Melbourne, Royal Melbourne Hospital, Melbourne, VIC, Australia
*
1Address for correspondence: Dr John T. O'Brien, Brighton Clinic, Newcastle General Hospital, Westgate Road, Newcastle upon Tyne NE4 6BE.
Get access Rights & Permissions [Opens in a new window]

Synopsis

Adrenal sensitivity was assessed in 16 non-depressed patients with NINCDS/ADRDA Alzheimer's disease (AD) and 18 control subjects by measuring cortisol response to low dose (0·05 μg/kg i.v.) exogenous adrenocorticotrophic hormone (ACTH). Controlling for sex and medication, both peak cortisol level (peak–baseline) and area under cortisol response curve (AUC above baseline) were significantly greater in AD subjects. This shows that HPA axis hyperactivity, as demonstrated by enhanced adrenal sensitivity to ACTH, occurs in AD. Similar findings have been reported to occur in depression. Among AD subjects, AUC cortisol response correlated with current age (r = 0·70, P = 0·001) and age at onset of dementia (r = 0·73, P = 0·001) and an inverse correlation was seen between cortisol AUC and cognitive test (CAMCOG) score (r = −0·51, P = 0·044). Our findings suggest that HPA axis hyperactivity in AD is associated with advancing age and cognitive dysfunction. Such changes may be cause, or consequence, of neuronal loss.

Type
Original Articles
Information
Psychological Medicine , Volume 26 , Issue 1 , January 1996 , pp. 7 - 14
Copyright
Copyright © Cambridge University Press 1996

Access options

Get access to the full version of this content by using one of the access options below. (Log in options will check for institutional or personal access. Content may require purchase if you do not have access.)

References

REFERENCES

Abou-Saleh, M. T., Spalding, E. M., Kellett, J. M. & Coppen, A. (1987). Dexamethasone suppression test in dementia. International Journal of Geriatric Psychiatry 2, 59–65.CrossRefGoogle Scholar
Aharon-Peretz, J., Harel, T., Revach, M. & Ben-Haim, S. A. (1992). Increased sympathetic and decreased parasympathetic cardiac innervation in patients with Alzheimer's disease. Archives of Neurology 49, 919–922.CrossRefGoogle ScholarPubMed
American Psychiatric Association (1987). Diagnostic and Statistical Manual of Mental Disorders 3rd edn. (Revised). APA: Washington, DC.Google Scholar
American Psychiatric Association Task Force (1987). The dexamethasone suppression test: an overview of its current status in psychiatry. American Journal of Psychiatry 144, 1253–1262.CrossRefGoogle Scholar
Ames, D., Flicker, L. & Helme, R. (1992). A memory clinic at a geriatric hospital: rationale, routine and results from the first 100 patients. Medical Journal of Australia 156, 618–622.CrossRefGoogle Scholar
Amsterdam, J. D., Maislin, G., Gold, P. & Winokur, A. (1989). The assessment of abnormalities in hormonal responsiveness at multiple levels of the hypothalamic-pituitary-adrenocortical axis in depressive illness. Psychoneuroendocrinology 14, 43–62.CrossRefGoogle ScholarPubMed
Ball, M. J., Fisman, M., Hachinski, V., Blume, W., Fox, A., Kral, V. A., Kirshen, A. J., Fox, H. & Merskey, H. (1985). A new definition of Alzheimer's disease: a hippocampal dementia. Lancet i, 14–16.CrossRefGoogle Scholar
Banki, C. M., Karmacsi, L., Bissette, G. & Nemeroff, C. B. (1992). Cerebrospinal fluid neuropeptides in mood disorder and dementia. Journal of Affective Disorders 25, 39–46.CrossRefGoogle ScholarPubMed
Carroll, B. J., Feinberg, M., Greden, J. F., Tarika, J., Albala, A. A., Haskett, R. F., James, N., Kronfol, Z., Lohr, N., Steiner, M., Vigne, J. P. & Young, E. (1981). A specific laboratory test for the diagnosis of melancholia. Archives of General Psychiatry 38, 15–22.CrossRefGoogle ScholarPubMed
Charlton, B. G. & Ferrier, I. N. (1989). Hypothalamo–pituitary–adrenal axis abnormalities in depression: a review and a model. Psychological Medicine 19, 331–336.CrossRefGoogle ScholarPubMed
De Souza, E. B., Bissette, G., Whitehouse, P. J., Powers, R. E., Price, D. L., Vale, W. W. & Nemeroff, C. B. (1990). In Corticotropin-Releasing Factor: Basic and Clinical Studies of a Neuropeptide (ed. De Souza, E. B. and Nemeroff, C. B.), pp. 175–189. CRC Press: Boca Raton, FL.Google Scholar
Estivariz, F. E., Lowry, P. J. & Jackson, S. (1992). Control of adrenal growth. In The Adrenal Gland (ed. James, V. H. T.), pp. 43–71. Raven Press: New York.Google Scholar
Fang, V. S., Jiang, H.-K., Rose, R. P. & Luchins, D. J. (1988). Adrenal gland in major depression: enlarged capacity or enhanced sensitivity? (letter). Archives of General Psychiatry 45, 964–965.CrossRefGoogle ScholarPubMed
Folstein, M., Folstein, S. & McHugh, P. (1975). ‘Mini-mental state’ a practical method for grading the cognitive state of patients for the clinician. Journal Psychiatric Research 12, 189–198.CrossRefGoogle Scholar
Franceschi, M., Airaghi, L., Gramigna, C., Truci, G., Manfred, M. G., Canal, N. & Catania, A. (1991). ACTH and cortisol secretion in patients with Alzheimer's disease. Journal of Neurology, Neurosurgery and Psychiatry 54, 836–837.CrossRefGoogle ScholarPubMed
Gehris, T. L., Kathol, R., Meller, W. H., Lopez, J. F. & Jaekle, R. S. (1991). Multiple steroid hormone levels in depressed patients and normal controls before and after exogenous ACTH. Psychoneuroendocrinology 16, 481–497.CrossRefGoogle ScholarPubMed
Georgotas, A., McCue, R. E., Kim, O. M., Hapworth, W. E., Reisberg, B., Stoll, P. M., Sinaiko, E., Fanelli, C. & Stokes, P. E. (1986). Dexamethasone suppression in dementia, depression and normal aging. American Journal of Psychiatry 143, 452–456.Google ScholarPubMed
Gold, P. W., Chrousos, G., Kellner, C., Post, R., Roy, A., Augerinos, P., Schulte, H., Oldfield, E. & Loriaux, D. L. (1984). Psychiatric implications of basic and clinical studies with corticotropin-releasing factor. American Journal of Psychiatry 141, 619–627.Google ScholarPubMed
Greenwald, B. S., Mathe, A. A., Mohs, R. C., Levy, M. I., Johns, C. A. & Davis, K. L. (1986). Cortisol and Alzheimer's disease, II: Dexamethasone suppression, dementia severity, and affective symptoms. American Journal of Psychiatry 143, 442–446.Google ScholarPubMed
Hamilton, M. (1967). Development of a rating scale for primary depressive illness. British Journal of Social and Clinical Psychology 6, 278–296.CrossRefGoogle ScholarPubMed
Heuser, I. J., Gotthardt, U., Schweiger, U., Schmider, J., Lammers, C. H., Dettling, M. & Holsboer, F. (1994). Age-associated changes of pituitary-adrenocortical hormone regulations in humans: importance of gender. Neurobiology of Ageing 15, 227–231.CrossRefGoogle ScholarPubMed
Jacobson, L. & Sapolsky, R. (1991). The role of the hippocampus in feedback regulation of the hypothalamic–pituitary–adrenocortical axis. Endocrine Reviews 12, 118–134.CrossRefGoogle ScholarPubMed
Jaeckle, R. S., Kathol, R. G., Lopez, J. F., Meller, W. H. & Krummel, S. J. (1987). Enhanced adrenal sensitivity to exogenous cosyntropin (ACTH 1–24) stimulation in major depression. Archives of General Psychiatry 44, 233–240.CrossRefGoogle ScholarPubMed
Katona, C. L. E. & Aldridge, C. R. (1985). The dexamethasone suppression test and depressive signs in dementia. Journal of Affective Disorders 8, 83–89.CrossRefGoogle ScholarPubMed
Keitner, G. I., Ryan, C. E., Kohn, R., Miller, I. W., Norman, W. H. & Brown, W. A. (1992). Age and the dexamethasone suppression test: results from a broad unselected patient population. Psychiatry Research 44, 9–20.CrossRefGoogle ScholarPubMed
Krishnan, K. R. R., Doraiswamy, P. M., Lurie, S. N., Figiel, G. S., Husain, M. M., Boyko, O. B., Ellinwood, E. H. & Nemeroff, C. B. (1991). Pituitary size in depression. Journal of Clinical Endocrinology and Metabolism 72, 256–259.CrossRefGoogle ScholarPubMed
Landon, J., James, V. H. T., Wharton, M. & Friedman, M. (1967). Threshold adrenocortical sensitivity in man and its possible application to corticotropin bioassay. Lancet ii, 697–700.CrossRefGoogle Scholar
Lesch, K. P., Ihl, R., Frolich, L., Rupprecht, R., Muller, U., Schulte, H. M. & Maurer, K. (1990). Endocrine responses to growth hormone releasing hormone and corticotropin releasing hormone in early-onset Alzheimer's disease. Psychiatry Research 33, 107–112.CrossRefGoogle ScholarPubMed
Lopez, J. F., Kathol, R. G., Jaeckle, R. S. & Meller, W. (1987). The HPA axis response to insulin hypoglycaemia in depression. Biological Psychiatry 22, 153–166.CrossRefGoogle ScholarPubMed
McKhann, G., Drachman, D., Folstein, M., Katzman, R., Price, D. & Stadlan, E. (1984). Clinical diagnosis of Alzheimer's disease: report of the NINCDS-ADRDA work group under the auspices of the Dept. of Health and Human Task Force in Alzheimer's Disease. Neurology 34, 939–944.CrossRefGoogle Scholar
Maes, M., Claes, M., Vandewoude, M., Schotte, C., Martin, M., Blockx, P. & Cosyns, P. (1992). Adrenocorticotropin hormone, β-endorphin and cortisol release to oCRH in melancholic patients. Psychological Medicine 22, 317–329.CrossRefGoogle Scholar
Maes, M., Meltzer, H., Cosyns, P., Calabrese, J., D'Hondt, P., Blockx, P., Vandervorst, C. & Raus, J. (1993). Pituitary and adrenal hormone responsiveness to synacthen in melancholic subjects versus subjects with minor depression. Biological Psychiatry 33, 624–629.CrossRefGoogle ScholarPubMed
Maguire, K. P., Tuckwell, V. M., Schweitzer, I., Tiller, J. W. G. & Davies, B. M. (1990). Dexamethasone kinetics in depressed patients before and after clinical response. Psychoneuroendocrinology 15, 113–123.CrossRefGoogle ScholarPubMed
Martignoni, E., Pertraglia, F., Costa, A., Bono, G., Genazzini, A. R. & Nappi, G. (1990). Dementia of the Alzheimer type and hypothalamopituitary–adrenocortical axis: changes in cerebrospinal fluid corticotropin releasing factor and plasma cortisol levels. Acta Neurologica Scandinavica 81, 452–456.CrossRefGoogle Scholar
May, C., Rapoport, S. I., Tomai, T. P., Chrousos, G. P. & Gold, P. W. (1987). Cerebrospinal fluid concentrations of corticotropin-releasing-hormone (CRH) and corticotropin (ACTH) are reduced in patients with Alzheimer's disease. Neurology 37, 535–538.CrossRefGoogle ScholarPubMed
Molchan, S. E., Hill, J. L., Martinez, R. A., Lawlor, B. A., Mellow, A. M., Rubinow, D. R., Bissette, G., Nemeroff, C. B. & Sunderland, T. (1993). CSF somatostatin in Alzheimer's disease and major depression: relationship to hypothalamic–pituitary–adrenal axis and clinical measures. Psychoneuroendocrinology 18, 509–519.CrossRefGoogle ScholarPubMed
Naito, Y., Fukata, J., Tamai, S., Seo, N., Nakai, Y., Mori, K. & Imura, H. (1991). Biphasic changes in hypothalamo–pituitary–adrenal function during the early recovery period after major abdominal surgery. Journal of Clinical Endocrinology and Metabolism 73, 111–117.CrossRefGoogle ScholarPubMed
Nemeroff, C. B., Krishnan, K. R. R., Reed, D., Leder, R., Beam, C. & Dunnick, R. (1992). Adrenal gland enlargement in major depression. A computed tomographic study. Archives of General Psychiatry 49, 384–387.CrossRefGoogle ScholarPubMed
Norušis, M. (1990). Statistical Package for the Social Sciences (SPSS/PC+). SPSS Inc: Chicago, USA.Google Scholar
O'Brien, J. T., Schweitzer, I., Ames, D., Mastwyk, M. & Colman, P. (1994 a). A study of HPA axis function in Alzheimer's disease: response to insulin hypoglycaemia. British Journal of Psychiatry 165, 650–657.CrossRefGoogle Scholar
O'Brien, J. T., Schweitzer, I., Ames, D., Tuckwell, V. & Mastwyk, M. (1994 b). Cortisol suppression by dexamethasone in the healthy elderly: effects of age, dexamethasone levels and cognitive function. Biological Psychiatry 36, 389–394.CrossRefGoogle ScholarPubMed
Powers, R. E., Walker, L. C., De Souza, E. B., Vale, W. W., Struble, R. G., Whitehouse, P. & Price, D. L. (1987). Immunohistochemical study of neurons containing corticotropin-releasing factor in Alzheimer's disease. Synapse 1, 405–410.CrossRefGoogle ScholarPubMed
Raadsheer, F. C., Oorschot, D. E., Verwer, R. W. H., Tilders, F. J. H. & Swaab, D. F. (1994 a). Age-related increase in the total number of corticotropin-releasing hormone neurons in the human paraventricular nucleus in controls and Alzheimer's disease: comparison of the disector with an unfolding method. Journal of Comparative Neurology 339, 447–457.CrossRefGoogle ScholarPubMed
Raadsheer, F. C., Tilders, F. J. H. & Swaab, D. F. (1994 b). Similar age related increase of vasopressin colocalisation in paraventricular corticotropin-releasing hormone neurons in controls and Alzheimer patients. Journal of Neuroendocrinology 6, 131–133.CrossRefGoogle Scholar
Reincke, M., Allolio, B., Wurth, G. & Winkelmann, W. (1993). The hypothalamic–pituitary–adrenal axis in critical illness: response to dexamethasone and corticotropin-releasing hormone. Journal of Clinical Endocrinology and Metabolism 77, 151–156.Google ScholarPubMed
Roth, M., Tym, E., Mountjoy, C., Huppert, F., Hendrie, H., Verma, S. & Goddard, R. (1986). CAMDEX: a standardised instrument for the diagnosis of mental disorder in the elderly with special reference to the early detection of dementia. British Journal of Psychiatry 149, 698–709.CrossRefGoogle Scholar
Sapolsky, R. M. & Plotsky, P. M. (1990). Hypercortisolism and its possible neural bases. Biological Psychiatry 27, 937–952.CrossRefGoogle ScholarPubMed
Sapolsky, R. M., Krey, L. C. & McEwen, B. (1986). The neuroendocrinology of stress and aging: the glucocorticoid cascade hypothesis. Endocrine Reviews 7, 284–301.CrossRefGoogle ScholarPubMed
Seckl, J. R. & Fink, G. (1992). Antidepressants increase glucocorticoid and mineralocortioid receptor expression. Neuroendocrinology 55, 621–626.CrossRefGoogle Scholar
Shrimankar, J., Soni, S. D. & McMurray, J. (1989). Dexamethasone suppression test in dementia and depression. British Journal of Psychiatry 154, 372–377.CrossRefGoogle ScholarPubMed
Weiner, M. F., Vobach, S., Svetlik, D. & Risser, R. C. (1993). Cortisol secretion and Alzheimer's disease progression – a preliminary report. Biological Psychiatry 34, 158–163.CrossRefGoogle ScholarPubMed
Wolkowitz, O. M., Reus, V. I., Manfredi, F., Ingbar, J., Brizendine, L. & Weingartner, H. (1993). Ketoconazole administration in hypercortisolemic depression. American Journal of Psychiatry 150, 810–812.Google ScholarPubMed